This study is aimed at gaining insight into the mechanism of bile formation and cholestatic liver injury and has the following specific objectives: (1) To identify which hepatic structures are involved in bile formation and what role they play in bile formation and stasis. The structures on which studies are to focused include (a) hepatocyte plasma membrane (bile canaliculus, lateral and sinusoidal surfaces) and its associated enzymes (e.g. adenosine triphosphase and alkaline phosphatase), (b) intercellular junctions, (c) the cytoskeletal system, (d) the Golgi apparatus, transport vesicles, lysosomes, endoplasmic reticulum and other organelles, and (e) bile ducts. (2) To study the relationship between the hepatic microcirculation and the zonal heterogeneity of hepatocytes with respect to bile acid metabolism, bile formation and cholestatic injury. (3) To study the relationship between the molecular structure of bile acids and their cholestatic and hepatotoxic potential. (4) To study the therapeutic potential of ursodeoxycholic acid in alleviating cholestatic injury. To achieve the first objective, acute cholestasis or choleresis will be induced in rats by the administration of cholestatic and choleretic agents (3.g bile acids) either singly or in combination. Bile duct ligation as well as biliary retention caused by choledocho-caval shunt will also be used. Morphological changes will be examined light and electron microscopically, including morphometry, enzyme histochemistry, use of electron opaque tracer materials, and freeze-fracture replica. Appropriate functional studies will be correlated with morphological studies. As regards the second objective, isolated rat livers will be perfused in normal or retrograde (hepatic to portal vein) direction and kinetic study on and autoradiography of bile acid uptake and secretion will be studied. Types and distribution of hepatic injuries induced by bile acids will also be correlated with the microcirculatory environment. To achieve the third objective, the effects of bile acids on bile formation and cholestasis, especially the 7-alpha and 7-beta stereoisomers of dihydroxy and monohydroxy bile acids, will be examined. Regarding the fourth objective, the effects of oral administration orsodeoxycholic acid on the cholestatic liver injuries induced by portal, total or selective biliary obstruction in the hamster will be examined.